This NCDDG Laboratory Program #2 led by Dr. Phil Crews (Department of Chemistry and Biochemistry, UC Santa Cruz). The project, Anti- cancer Leads from Marine sponges and their Bacterial Associants, will continue to explore the natural products of bioactive coral reef sponge extracts. New elements added to the research plan include: obtaining sponges from remote geographical locations, prioritizing less studied taxa, emphasizing sponges rich in heterotrophic associants, and obtaining sponge derived bacteria for saltwater culture. Molecular target-based assays serve as a key element guiding the isolation of actives which are then fully characterized and presented as leads for further development. This grant seeks continuation of a successful project. Leading our recent achievements is the contribution of exceptional lead compounds: the bengamides, the psammaplins, and the fascaplysins. Each family is in various stages of development by our NCDDG Pharmaceutical partner. Most significantly, a non-obvious synthetic bengamide analog (discrete structure) is scheduled for a clinical trial in May 2000. The aims of the renewal project are divided into categories as follows: (1) To continue the study of our repository of Indo-Pacific sponges and extracts for novel active compounds. (2) To use database mining accompanied by annual expeditions to select and obtain new sponges for study while placing emphasis on those that are unique or belong to under- explored taxonomic classes. (3) To expand the biodiversity of sponge material by conducting expeditions to new coral reef study sites. (4) To expand the chemodiversity of extracts by placing particular emphasis on sponges that are rich in bacterial populations. (6) To utilize newly developed molecular target-based assays to identify extracts for further fractionation. (7) To efficiently isolate secondary metabolites from active crude extracts guided by high throughput screens (NTSs) accompanied by pre-fractionation and state-of-the-art dereplication methods. (8) To use recently developed NMR and MS methods to accelerate the total structure elucidation of new active compounds. (9) To engage in lead optimization by initiating scale-up reisolation of macro-organism metabolites or scale- up cultures of microorganisms. (10) To obtain patent coverage for important new active compounds.